Apoptosis is a genetically programmed cell death and its deregulation is associated among other pathologies, with cancer. While apoptosis is known to rely on the Bcl-2 family members and caspases, recent data suggested that two major families of serine/threonine phosphatases, PP1 and PP2A, are key actors involved in cell life or cell death decision. The Ser/Thre phosphatase PP2A has been implicated in both, induction and prevention of apoptosis, pointing to a complex interplay of phosphatase actions. Several phosphatases have recently become attractive targets for the treatment of a variety of diseases, including cancers. However, the only clinical drugs targeting a phosphatase are the immunosuppressive cyclosporine A and FK506.
Cell penetrating peptides (CPP) are molecules which can translocate into cells without causing membrane damage, leading to their proposed use as vectors for delivering therapeutic cargo. Several CPP have been identified such as Tat, antennapedia, or SHV1 VP22. These peptides can cross the cell membrane and reach the cytoplasm and/or the nucleus. Penetrating peptides interacting with PP1/PP2A proteins were designed. This approach, named “Drug Phosphatase Technology” (DPT), was described in Guergnon et al, 2006 and International patent applications WO2003/011898 and WO2004/011595. A pro-apoptotic peptide, called DPT-C9h, that specifically deregulates the interaction between caspase-9 and PP2A, used this penetrating sequence (international patent application WO2010/112471).
However this peptide shows a short half-life, which is a real draw-back for clinical uses.